Innate Immune Activation and Mitochondrial ROS Invoke Persistent Cardiac Conduction System Dysfunction after COVID-19 (preprint)

BackgroundCardiac risk rises during acute SARS-CoV-2 infection and in long COVID syndrome in humans, but the mechanisms behind COVID-19-linked arrhythmias are unknown. This study explores the acute and long term effects of SARS-CoV-2 on the cardiac conduction system (CCS) in a hamster model of COVID-19. MethodsRadiotelemetry in conscious animals was used to non-invasively record electrocardiograms and subpleural pressures after intranasal SARS-CoV-2 infection. Cardiac cytokines, interferon-stimulated gene expression, and macrophage infiltration of the CCS, were assessed at 4 days and 4 weeks post-infection. A double-stranded RNA mimetic, polyinosinic:polycytidylic acid (PIC), was used in vivo and in vitro to activate viral pattern recognition receptors in the absence of SARS-CoV-2 infection. ResultsCOVID-19 induced pronounced tachypnea and severe cardiac conduction system (CCS) dysfunction, spanning from bradycardia to persistent atrioventricular block, although no viral protein expression was detected in the heart. Arrhythmias developed rapidly, partially reversed, and then redeveloped after the pulmonary infection was resolved, indicating persistent CCS injury. Increased cardiac cytokines, interferon-stimulated gene expression, and macrophage remodeling in the CCS accompanied the electrophysiological abnormalities. Interestingly, the arrhythmia phenotype was reproduced by cardiac injection of PIC in the absence of virus, indicating that innate immune activation was sufficient to drive the response. PIC also strongly induced cytokine secretion and robust interferon signaling in hearts, human iPSC-derived cardiomyocytes (hiPSC-CMs), and engineered heart tissues, accompanied by alterations in electrical and Ca2+ handling properties. Importantly, the pulmonary and cardiac effects of COVID-19 were blunted by in vivo inhibition of JAK/STAT signaling or by a mitochondrially-targeted antioxidant. ConclusionsThe findings indicate that long term dysfunction and immune cell remodeling of the CCS is induced by COVID-19, arising indirectly from oxidative stress and excessive activation of cardiac innate immune responses during infection, with implications for long COVID Syndrome.

Electrocardiographic changes in hospitalised children with COVID-19.

OBJECTIVES: Cardiac manifestations of the coronavirus disease 2019 (COVID-19) have mainly been reported in adults. Therefore, we aimed to determine the electrocardiographic abnormalities in hospitalised paediatric patients with COVID-19 and multisystemic inflammatory syndrome in children. METHODS: We retrospectively evaluated hospitalised paediatric patients <18 years of age with a diagnosis of COVID-19 (n = 168) and multisystem inflammatory syndrome in children (n = 48) between March 2021 and December 2021. A daily electrocardiography was performed for the patients who had electrocardiographic abnormalities on admission or developed electrocardiographic abnormality on the follow-up. The characteristics of these patients, underlying predisposing conditions, and clinical course were also examined. RESULTS: Two-hundred sixteen paediatric patients (55% were male) with a mean age of 10.7 ± 4.69 years were evaluated. There was an underlying disease in 84 (38.8%) patients and 51 (23.6%) required paediatric ICU admission. Electrocardiography abnormality was detected in 12 (5.5%) which were as follows: 7 (3.2%) had sinus bradycardia, 3 (1.4%) patients had transient ST elevation and concomitant T negativity, and 2 (0.9%) developed first-degree Atrioventricular (AV) block. The median time from the onset of disease symptoms to detecting electrocardiographic abnormality was 9 days. Electrocardiographic abnormalities returned to normal uneventfully 3 days later. CONCLUSIONS: The prevalence of arrhythmia in paediatric patients with COVID-19 was detected in 5.5% of the patients. While two-thirds of the electrocardiography abnormalities were sinus bradycardia, ST elevation was remarkable (1.4%). Clinicians should be aware of electrocardiographic abnormalities and consider electrocardiographic monitoring in paediatric patients with COVID-19 and multisystemic inflammatory syndrome in children.

Complete atrioventricular block due to multisystem inflammatory syndrome in children: a case report.

BACKGROUND: Cardiac manifestations in multisystem inflammatory syndrome in children (MIS-C) may involve the conduction system. The incidence and publication is still very limited. CASE: We report the case of a 2-year-old girl who presented with complete atrioventricular (AV) block with a current infection of SARS-CoV-2 and fulfilled the criteria of MIS-C. After observation for 2 weeks of the SARS-CoV-2 convalescence phase and temporary pacemaker insertion, the complete AV block was not resolved. The intrinsic junctional escape beat was only 40 beats/minute. We decided to implant a dual-chamber epicardial permanent pacemaker to maintain synchrony between atrium and ventricle and furthermore provide hemodynamic stability. We observed persistent complete AV block 9 months after SARS-CoV-2 infection in long-term follow up of this patient. CONCLUSIONS: Complete AV block in MIS-C could persist months after its onset. Our case could give additional knowledge regarding the natural history of cardiac involvement after SARS-CoV-2 infection.

High degree atrio-ventricular block following COVID-19 vaccination.

BACKGROUND: The coronavirus disease 2019 (COVID-19) pandemic has resulted in more than four million deaths globally. In addition to the lower respiratory system, a wide range of major organ injuries have been reported among patients infected with COVID-19. These injuries include cardiac involvement. The spectrum of cardiac manifestations includes cardiac injury, heart failure, cardiogenic shock, acute coronary syndrome, myocarditis, tachyarrhythmias, and bradyarrhythmia [1]. Different degrees of atrioventricular blocks have been reported [2]. The pathogenesis of these complications is not fully understood. Different mechanisms are proposed, including direct myocyte injury, interstitial inflammation and fibrosis, cytokine storm, plaque destabilization, and and/or hypoxia [3]. Many countries have worked toward mass vaccination using the Pfizer BioNTech (BNT162b2) COVID-19 vaccine, including Israel. We report a case of high degree atrioventricular block (AVB) following vaccination with the COVID-19 BNT162b2 vaccine.

Usefulness of Temporary Pacing in Patients With New Left Bundle Branch Block During Transcatheter Aortic Valve Implantation.

New-onset left bundle branch block (NLBBB) is the most common complication after transcatheter aortic valve implantation (TAVI). Expert consensus recommends temporary transvenous pacemaker (TTVP) support for 24 hours in these patients. To date, no study has examined TTVP use during the index hospitalization in detail. Therefore, we aimed to assess TTVP use in patients with TAVI who developed NLBBB. In this prospective observational study, we performed a detailed analysis of 24-hour telemetry in patients who developed NLBBB during TAVI. Baseline characteristics and procedural and postprocedural data were recorded. The primary outcome was pacing by the TTVP. We evaluated inappropriate TTVP use, electrophysiology study findings, permanent pacemaker (PPM) implantation, and NLBBB resolution. A total of 83 patients (74.4 ± 8.7 years, 41% female) developed NLBBB during TAVI. During index hospitalization, 1 patient (1%) required TTVP because of complete heart block and received a PPM. Five of the 83 (6%) patients were inappropriately paced, and 1 patient (1%) had ventricular fibrillation, likely secondary to TTVP. A total of 34 patients (41%) underwent electrophysiology study during hospitalization, with 4 of 83 (5%) subsequently receiving a PPM. One (1%) patient died during hospitalization, and 9 patients were lost to follow-up because of the COVID-19 pandemic. Of the remaining 73 patients with a 30-day follow-up, NLBBB had resolved in 36 (49%) at 30 days, and 2 (3%) were readmitted with complete heart block and received PPM. In conclusion, in patients with TAVI who develop NLBBB, temporary pacing is rarely necessary, may carry additional risks to the patient, and prolong hospitalization time.

Characteristics of bradyarrhythmia in patients with COVID-19: Systematic scoping review.

COVID-19 has recently been associated with the development of bradyarrhythmias, although its mechanism is still unclear. We aim to summarize the existing evidence regarding bradyarrhythmia in COVID-19 and provide future directions for research. Following the PRISMA Extension for Scoping Reviews, we searched MEDLINE and EMBASE for all peer-reviewed articles using keywords including"Bradycardia," "atrioventricular block," and "COVID-19″ from their inception to October 13, 2021. Forty-three articles, including 11 observational studies and 59 cases from case reports and series, were included in the systematic review. Although some observational studies reported increased mortality in those with bradyarrhythmia and COVID-19, the lack of comparative groups and small sample sizes hinder the ability to draw definitive conclusions. Among 59 COVID-19 patients with bradycardia from case reports and series, bradycardia most often occurred in those with severe or critical COVID-19, and complete heart block occurred in the majority of cases despite preserved LVEF (55.9%). Pacemaker insertion was required in 76.3% of the patients, most of which were permanent implants (45.8%). This systematic review summarizes the current evidence and characteristics of bradyarrhythmia in patients with COVID-19. Further studies are critical to assess the reversibility of bradyarrhythmia in COVID-19 patients and to clarify potential therapeutic targets including the need for permanent pacing.

Complete heart block, severe right ventricular dysfunction in a child with COVID-19 infection.

A young child presented with hepatomegaly, ascites and bradycardia in the setting of COVID-19. Permanent complete atrioventricular block and severe right heart failure were diagnosed. He was treated with surgical epicardial pacemaker implantation. This report is the first description of COVID-19-induced permanent complete atrioventricular block in a child.

Unravelling Atrioventricular Block Risk in Inflammatory Diseases: Systemic Inflammation Acutely Delays Atrioventricular Conduction via a Cytokine-Mediated Inhibition of Connexin43 Expression.

Background Recent data suggest that systemic inflammation can negatively affect atrioventricular conduction, regardless of acute cardiac injury. Indeed, gap-junctions containing connexin43 coupling cardiomyocytes and inflammation-related cells (macrophages) are increasingly recognized as important factors regulating the conduction in the atrioventricular node. The aim of this study was to evaluate the acute impact of systemic inflammatory activation on atrioventricular conduction, and elucidate underlying mechanisms. Methods and Results We analyzed: (1) the PR-interval in patients with inflammatory diseases of different origins during active phase and recovery, and its association with inflammatory markers; (2) the existing correlation between connexin43 expression in the cardiac tissue and peripheral blood mononuclear cells (PBMC), and the changes occurring in patients with inflammatory diseases over time; (3) the acute effects of interleukin(IL)-6 on atrioventricular conduction in an in vivo animal model, and on connexin43 expression in vitro. In patients with elevated C-reactive protein levels, atrioventricular conduction indices are increased, but promptly normalized in association with inflammatory markers reduction, particularly IL-6. In these subjects, connexin43 expression in PBMC, which is correlative of that measured in the cardiac tissue, inversely associated with IL-6 changes. Moreover, direct IL-6 administration increased atrioventricular conduction indices in vivo in a guinea pig model, and IL-6 incubation in both cardiomyocytes and macrophages in culture, significantly reduced connexin43 proteins expression. Conclusions The data evidence that systemic inflammation can acutely worsen atrioventricular conduction, and that IL-6-induced down-regulation of cardiac connexin43 is a mechanistic pathway putatively involved in the process. Though reversible, these alterations could significantly increase the risk of severe atrioventricular blocks during active inflammatory processes.

Incidence of Atrioventricular Blocks and its Association with In-Hospital Mortality and Morbidity in Patients with Coronavirus Disease 2019.

BACKGROUND: Cardiovascular sequelae of coronavirus disease 2019 (COVID-19) infection have been explored by clinicians and researchers all over the world. OBJECTIVE: The purpose of this study was to evaluate the incidence of atrioventricular block (AV) in patients hospitalized for COVID-19 and its association between in-hospital morbidity and mortality. METHODS: In-hospital electrocardiograms (ECGs) of 438 patients were compared with their prior or baseline ECGs to ascertain the development of new onset AV block. Patients who developed new AV blocks were then followed at 30 and 90 days post-discharge to check for resolution of AV block. Demographic characteristics, clinical characteristics, and complications during their hospital stay were evaluated. Major complications including respiratory failure requiring oxygen supplementation and mechanical ventilation, sepsis, deep vein thrombosis, elevated troponins, hospital and intensive care unit (ICU) length of stay, as well as death were compared between those who developed new onset AV blocks and those who did not. RESULTS: Based on our single center study, the incidence of new onset AV blocks among patients admitted for COVID-19 during the study period was 5.5 cases per 100 patients. New onset AV blocks were not associated with longer hospital and ICU length of stay, increased intubation rates, or increased mortality. CONCLUSION: Although the development of a new onset AV block is most likely multifactorial and not solely due to COVID-19, it is still important for clinicians to be mindful about the possibility of developing symptomatic bradycardia and life-threatening arrhythmias in patients admitted for COVID-19. This can be achieved by appropriate rhythm monitoring in-patient but the need for a cardiac event monitor upon discharge is unlikely to be necessary. Careful history taking, including family and drug use history is also of great importance as emerging drug therapies for COVID-19 have potential arrhythmogenic effects.

Implantation of cardiac electronic devices in active COVID-19 patients: Results from an international survey.

BACKGROUND: Cardiac implantable electronic device (CIED) implantation rates as well as the clinical and procedural characteristics and outcomes in patients with known active coronavirus disease 2019 (COVID-19) are unknown. OBJECTIVE: The purpose of this study was to gather information regarding CIED procedures during active COVID-19, performed with personal protective equipment, based on an international survey. METHODS: Fifty-three centers from 13 countries across 4 continents provided information on 166 patients with known active COVID-19 who underwent a CIED procedure. RESULTS: The CIED procedure rate in 133,655 hospitalized COVID-19 patients ranged from 0 to 16.2 per 1000 patients (P <.001). Most devices were implanted due to high-degree/complete atrioventricular block (112 [67.5%]) or sick sinus syndrome (31 [18.7%]). Of the 166 patients in the study survey, the 30-day complication rate was 13.9% and the 180-day mortality rate was 9.6%. One patient had a fatal outcome as a direct result of the procedure. Differences in patient and procedural characteristics and outcomes were found between Europe and North America. An older population (76.6 vs 66 years; P <.001) with a nonsignificant higher complication rate (16.5% vs 7.7%; P = .2) was observed in Europe vs North America, whereas higher rates of critically ill patients (33.3% vs 3.3%; P <.001) and mortality (26.9% vs 5%; P = .002) were observed in North America vs Europe. CONCLUSION: CIED procedure rates during known active COVID-19 disease varied greatly, from 0 to 16.2 per 1000 hospitalized COVID-19 patients worldwide. Patients with active COVID-19 infection who underwent CIED implantation had high complication and mortality rates. Operators should take these risks into consideration before proceeding with CIED implantation in active COVID-19 patients.

Conduction System Disease and Atrioventricular Block in Victims of COVID-19 in Iran (preprint)

Background: More recently, a growing body of literature on COVID-19 has investigated the electrophysiological issues presetting as a disease manifestation of COVID-19 and highlight the spectrum of arrhythmias observed in patients with COVID-19 infection. This Study discuss the prevalence of arrhythmias and conduction system disease in patients with COVID-19. Method electrocardiographic data and comorbidity data of 432 expired COVID-19 patients admitted to Faghihi Hospital of Shiraz University of Medical Sciences from August 1st until December 1st were reviewed. Results AVB was found in 40(9.3%) patients. 28(6.5%) of the patients suffered from 1st degree AVB, and 12(2.8%) suffered from CHB. Changes in ST-T wave compatible with myocardial infarction or localized myocarditis appeared in 189(59.0%) patients. Findings compatible with myocardial injury such as fragmented QRS, and prolonged QTc were assessed with prevalence of 21.1% (91 patients), 6.5% (28 patients). In victims of COVID-19, conduction disease was not related to any underlying medical condition. Fragmented QRS, axis deviation, presence of S1Q3T3 and poor R wave progression were significantly related to conduction system disease in victims of COVID-19 (P value > 0.05, Table 3) Conclusion Our findings can serve in future studies that aim to develop a risk stratification method for susceptible COVID-19 patients. Myocardial injury appears to role significantly in COVID-19 morbidity and mortality. Consequently, we recommend health policymakers to consider separate catheterization laboratories that provide service only to COVID-19 patients.

Implementation of a practice plan for the outpatient cardiac evaluation of children after acute SARS-CoV-2 infection and a report of outcomes.

SARS-CoV-2 infection has been associated with cardiovascular disease in children, but which children need cardiac evaluation is unclear. We describe our experience evaluating 206 children for cardiac disease following SARS-CoV-2 infection (one of whom had ventricular ectopy) and propose a new guideline for management of these children. Routine cardiac screening after SARS-CoV-2 infection in children without any cardiac signs or symptoms does not appear to be high yield.

Paroxysmal Atrioventricular Block in a Relatively Young Patient with COVID-19.

Cardiac involvement has been reported in patients with coronavirus disease 2019 (COVID-19). We herein report a 41-year-old man who presented with recurrent paroxysmal atrioventricular block without showing significant cardiac injuries or comorbidities. The patient was diagnosed with COVID-19 and admitted to our hospital, where he was noted to have paroxysmal atrioventricular block. Cardiac biomarkers, echocardiography, and cardiac magnetic resonance imaging findings were fairly normal. An endomyocardial biopsy performed before the implantation of a permanent pacemaker revealed mild myocardial fibrosis without inflammatory infiltrates. The unusual myocardial involvement of the novel coronavirus was suspected.